The overall hypothesis that guides our research is that molecular regulators of pancreatic organogenesis, originally deployed in the embryo, remain relevant to adult disease processes. Among these regulators is the Notch signaling pathway, which the PI has previously studied in an embryonic context. Based on a recent NCI Program Announcement, seeking proposals for pilot studies in pancreatic cancer (PA-06- 303), we have begun to investigate the role of Notch signaling in pancreatic cancer. Notch acts to inhibit differentiation in the developing pancreas; although Notch pathway activation has been detected in human pancreatic cancer, its role there has not yet been determined. Notch activation is also observed in the precancerous lesions that form in a mouse model of this disease, driven by activation of the K-ras oncogene. Our preliminary evidence indicates that Notch activation dramatically sensitizes pancreatic progenitor cells to K-ras-induced dysplasia, and we hypothesize that Notch signaling in the adult drives dedifferentiation to a progenitor-like state that is similarly susceptible to K-ras. Here, we propose two Specific Aims to study the role of Notch signaling in initiation and progression of pancreatic cancer. (1) We will activate K-ras and/or Notch signaling in differentiated cells of the adult mouse pancreas, and determine whether the pathways synergistically promote the formation of precancerous lesions. (2) We will determine the requirement for continued Notch signaling in initiation, progression and maintenance of pancreatic cancer, applying independent loss-of-function approaches to intact mice as well as cultured human pancreatic cancer cells. In addition to guiding future mechanistic studies of Notch and K-ras synergy, we anticipate that the outcome of this work will be of considerable clinical relevance, given that the Notch pathway is a potential target for pharmacological inhibition in humans. [unreadable] Public Health Relevance: This proposal seeks to implicate or exclude the Notch signaling pathway as a potential drug target in pancreatic cancer. In addition, it will shed new light on the cellular and molecular origins of this deadly human disease. The research described in this application is 100% relevant to pancreatic cancer. [unreadable] [unreadable] [unreadable]